Hepatocellular carcinoma (HCC) accounts for 80-90%of liver cancer diagnosed in adult oncology and thus accounts for significant morbidity and mortality in the United States. A major mechanism of HCC resistance and ability of cancer cells to thwart treatments relies on the PI-3 kinase and Myc cell signaling pathways. We have generated preliminary data which suggest that a dual pan PI-3 kinase/BRD4 inhibitor, SF1126 has potent antitumor activity in vitro and in vivo against HCC and inhibits the BRD4-Myc interaction. These data support the hypothesis that dual PI3K/BRD4 inhibitors will have activity in the treatment of advanced HCC. Based on SEER database published in 2010 (www.SEER.org) the prevalence of HCC is 41,404 in the US. Currently, the only curative treatment for HCC is complete surgical resection or liver transplantation. The significance of our proposal derives from the unmet medical need for alternative therapy for patients with recurrent, unresectable, and/or metastatic HCC (termed advanced HCC). If successful, this therapy could provide a significant advancement in the quality of treatment and quality of life for this difficult to treat disease. A previous Phase I trial of a dual PI3K/BRD4 inhibitor, SF1126 (an integrin targeted prodrug small molecule) (partly supported by the NIH RO1 CA94233) was carried out in 39 non-genotyped patients diagnosed with recurrent adult solid tumors (including colon cancer, renal cell carcinoma, and recurrent breast cancer) and 5 patients with B-cell malignancy. SF1126 was well-tolerated and demonstrated complete pathway inhibition in tumor biopsies. Importantly, SF1126 displayed no hepatotoxicity in this Phase I trial. Clinical benefit was observed in the form of prolonged stable disease for up to 84 weeks duration. Stable disease was the best response in 19 of 33 patients (58%) evaluable patients with median duration of 13 weeks and mean of 18 weeks. MTD was not reached but the maximum administered dose (MAD) after 9 dose escalation cohorts was 1110 mg/m2 and this dose was chosen as the recommended Phase II dose (RMP2). The results of the Phase I trial justify a Phase I evaluation of SF1126 in HCC. We propose 3 specific aims to test the hypothesis that SF1126 will be efficacious in advanced HCC. The specific aims are designed: 1) to determine the toxicity profile of SF1126 in order to determine the RMP2 dose level in the treatment of advanced HCC patients including patients classified as Child-Pugh A-B7 with liver dysfunction/cirrhosis; 2) to evaluate mechanisms of resistance in HCC cell lines and tumor models and 3) to validate and compare the observed resistance mechanisms confirmed in Aim 2-3 to the TCGA-ICGC molecular and clinical dataset of 1094 HCC tumors in preparation for planned Phase II trial. An innovative component of this proposal derives from this being one of the first clinical trials of a novel PI-3 kinase/BRD4 inhibitor in a Phase I HCC trial and our efforts to use sophisticated molecular methods to identify a molecular signature in HCC model systems which may identify factors which define resistance or sensitivity to this class of agent in future Phase II trials.